Gonadotropin releasing hormone (known as a luteinizing hormone releasing hormone) is a decapeptide which is secreted from the hypothalamus and affects receptors located in the anterior pituitary gland to stimulate biosynthesis and secretion of luteinizing hormones (LH) and follicle-stimulating hormones (FSH). Luteinizing hormone modulates the synthesis of steroids from genital glands in both males and females. It participates in the development of spermatogenesis in males and follicle in females. Thus, much attention has been given to GnRH receptor agonists or antagonists as a therapeutic agent for hormone-related diseases, especially, prostate cancer, breast cancer, endometriosis, uterine myoma, precocious puberty and the like, as well as infertility.
There are two different modes of action for the therapeutic agents that are currently being used. In one mode of action, the therapeutic agent acts as a GnRH antagonist that requires continuous administration which depletes gonadotropins and downregulates the receptors, thereby causing suppression of steroidal hormones approximately after 2 to 3 weeks following the initiation of continuous administration. However, it is inevitable to undergo superagonism in the beginning, thus there is an inconvenience that patients must go through initial side effects in this mode.
In the other mode of action, it directly acts as a GnRH antagonist so that it can suppress gonadotropins from the onset. This mechanism may reduce the level of gonadotropin directly without causing initial side effects. However, it was found in clinical studies that GnRH antagonists showed relatively low bioavailability and adverse side effects caused by histamine release. Although, there have been reported peptidic antagonist having low histamine release properties, they still must be delivered via parental administration routes (e.g., intravenous, subcutaneous and intramuscular injection) due to limited bioavailability.
Accordingly, there has been suggested a nonpeptide antagonist to overcome the limitations associated with peptidic GnRH antagonists (Sarma, P K S, Expert Opin. Ther. Patents 16(6): 733-751, 2006). However, there still remains a need for a low-molecular GnRH receptor antagonist having good bioavailability despite intensive research studies in this field.